Method of treating or preventing tumors of the central nervous system

ABSTRACT

The invention provides methods and compositions for treatment of a subject with a central nervous system (CNS) tumor comprising administration of Coenzyme Q10 (CoQ10), particularly when the subject exhibits at least one CNS abnormality as a result of the tumor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 13/439,615 filed Apr. 4, 2012, which, in turn,claims priority to U.S. Provisional Application Ser. No. 61/471,659,filed on Apr. 4, 2011. The applications are incorporated herein byreference in their entirety.

BACKGROUND

Central nervous system (CNS) tumors include tumors present in the brain,spinal cord, or the lining around such structures (e.g., meninges andSchwann cells) or eye. Tumors of the CNS may be categorized as primaryCNS tumors or secondary CNS tumors. Primary CNS tumors are neoplasmsthat originate in the CNS. Secondary CNS tumors, the most common form ofbrain tumors, originate outside of the CNS and result from the primarytumor metastasizing to the CNS. Secondary CNS tumors can either involvethe brain directly (i.e., parenchymal involvement) or involve the lining(i.e., leptomeningeal and meningeal involvement). In adults, solidtumors that have been shown to frequently metastasize to the CNS includelung, breast, adenocarcinoma of unknown primary site, melanoma, renal,and colon cancer. In children, primary solid tumors that more commonlymetastasize to the CNS include sarcoma, Wilm's tumor, neuroblastoma, andgerm cell tumor. In addition to solid tumors, haematologicalmalignancies that can metastasize to the CNS include acute lymphoblasticleukemia, high grade non-Hodgkin's lymphoma, and less commonly acutemyeloid leukemia.

Treatment of primary and secondary CNS tumors depends on themultiplicity, location, and grade of the tumor. Treatment of secondaryCNS tumors may also depend upon the status of the systemic tumor.Treatment may include any of surgical resection, stereotacticradiosurgery (SRS), whole brain radiotherapy (WBRT) and chemotherapy orsome combination thereof. Treatment of brain tumors faces a uniquechallenge compared to other types of cancers, due to the fact that notonly are they developed within bone-covered structures, thereby havingrestricted space to expand, but they are also embedded deeply within anorgan carrying a multitude of vital functions. Therefore, even a benigntumor can be life-threatening if it is in an area of the brain thatcontrols critical body functions such as breathing or blood circulation.Treatment normally begins with surgical resection and then follows withradiation or chemotherapy. Surgery faces the risk of removingsurrounding tissues that may carry vital brain functions, whileradiation and chemotherapy can both harm normal tissues that are near oralong the treatment path. Indeed, surgery usually is not recommended ifthe tumor is in regions of cerebral hemispheres that control speech,vision, movement or cognition. In addition, the use of radiation onchildren under the age of three is often prohibited because this is acritical time period of brain development. Efficacy of chemotherapy issomewhat limited due to frequent limited duration of effects and lack oftargeting and selectivity of the drugs.

The inability of many conventional chemotherapeutic agents to cross theblood-brain barrier (BBB) has historically limited their use in thetreatment of CNS tumors. The BBB is formed by the complex tightjunctions between the endothelial cells of the brain capillaries andtheir low endocytic activity (Potschka et al., Journal of Pharm. andExp. Therapeutics 306(1):124-131, 2003 July). This results in acapillary wall that behaves as a continuous lipid bilayer and preventsthe passage of polar and lipid-insoluble substances. Additionally,ATP-dependent multidrug transporters such as P-glycoprotein (Pgp; ABCB1)and multidrug resistance protein MRP2 (ABCC2), which are found in themembranes of brain capillary endothelial cells, are thought to play animportant role in BBB function by limiting drug penetration into thebrain. It is, therefore, an obstacle to drugs that may combat diseasesaffecting the CNS.

SUMMARY OF THE INVENTION

The invention provides methods and compositions for treatment of asubject with a central nervous system (CNS) tumor comprisingadministration of a Coenzyme Q10 (CoQ10) compound, particularly when thesubject exhibits at least one CNS abnormality as a result of the tumor.

The invention provides methods of treating a central nervous system(CNS) tumor in a subject exhibiting at least one CNS abnormalitycomprising administering to the subject a composition comprising aCoenzyme Q10 (CoQ10) compound, thereby treating the CNS tumor.

In certain embodiments, the CNS abnormality is one or more (e.g., 1, 2,3, 4, 5, 6, 7, 8, 9, 10 or more) of a headache, a seizure, a change inmemory especially loss of short term memory, a change in temperament,sudden onset of panic attacks induced by familiar situations, a changein intellectual function, inability to do math or find objects in plainsight; confusion, disorientation, becoming lost in a familiar location;blurred vision, loss of vision, loss of peripheral vision, doublevision, dizziness, hearing problems, ringing in ears, buzzing in ears,seizure, decreased muscle control, lack of coordination, decreasedsensation, weakness, paralysis, paraplegia, quadriplegia, difficultywith walking or change in gait, difficulty with speech, and balanceproblems. In certain embodiments, treatment results in amelioration ofat least one CNS abnormality. In certain embodiments, at least one CNSabnormality comprises at least 2, at least 3, at least 4, at least 5, atleast 6, at least 7, at least 8, at least 9, at least 10, at least 15,or at least 20 CNS abnormalities. In certain embodiments, at least oneCNS abnormality comprises 2-10 CNS abnormalities, 3-10 CNSabnormalities, 4-10 CNS abnormalities, 5-10 CNS abnormalities, 5-15 CNSabnormalities, 6-15 CNS abnormalities, 7-15 CNS abnormalities, 8-20 CNSabnormalities, 10-20 CNS abnormalities.

In certain embodiments, the tumor is a primary tumor. In certainembodiments, the tumor is a metastatic tumor.

The invention provides methods of prevention or treatment of a secondaryCNS tumor from a primary tumor in a subject comprising administering tothe subject a composition comprising a Coenzyme Q10 (CoQ10) compound,thereby preventing or treating the secondary CNS tumor.

In certain embodiments, the primary tumor is a pediatric tumor. Incertain embodiments, the pediatric tumor is a leukemia.

In certain embodiments, the primary tumor was treated with CNSradiation. In certain embodiments, the primary tumor was treated byadministration of a chemotherapeutic agent to the CNS. In certainembodiments, administration of chemotherapy to the CNS comprisesintrathecal administration of the chemotherapeutic agent.

In certain embodiments, the methods further comprise monitoring thesubject for development of a secondary CNS tumor.

In certain embodiments, the subject is in remission for the primarytumor. In certain embodiments, the secondary tumor is identified atleast one year after treatment is concluded. In certain embodiments, thesecondary tumor is identified at least three years after treatment isconcluded. In certain embodiments, the secondary tumor is identified atleast five years after treatment is concluded. In certain embodiments,the secondary tumor is identified at least ten years after treatment isconcluded.

In certain embodiments, the CoQ10 compound CoQ10.

In certain embodiments, the CNS tumor is in the subject at a locationselected from the group consisting of brain, spinal cord, lining of thebrain, lining of the spinal cord, and eye, or a combination thereof. Incertain embodiments, the CNS tumor is a tumor selected from the groupconsisting of a tumor of neuroepithelial tissue, a tumor of cranial andparaspinal nerves, a tumor of the meninges, a tumor of thehaematopoietic system, a germ cell tumor, a tumor of the sellar region,a lymphatic tumor, a leukemic tumor, a melanocytic tumor, a carcinomatumor, and a sarcoma tumor.

In certain embodiments, the tumor is a leukemic tumor. In certainembodiments, the leukemic tumor is selected from the group consisting ofchlorleukemic tumor, acute lymphoblastic leukemia (ALL) tumor, acutemyelogenous leukemia (AML) tumor, acute promyelogenous leukemia tumor,and mixed lineage leukemia tumor.

In certain embodiments, the CoQ10 compound is administered orally.

In certain embodiments, the CoQ10 compound is administered topically.

In certain embodiments, the CoQ10 compound is administered parenterally.

In certain embodiments, the CoQ10 compound is administered by injectionor infusion.

In certain embodiments, the CoQ10 compound is administered by a routeselected from the group consisting of subcutaneously, intravenously,intramuscularly, intratumorally, intrathecally, intracranially,intraperitoneally, transcutaneously, intramedullaryly, intrathecally,intraventricularly, intraperitoneally, intraocularly, and intranasally.

In certain embodiments, the CoQ10 compound is not administered directlyto the CNS. In certain embodiments, the CoQ10 compound is notadministered intrathecally, intratumorally, intracranially,intramedullaryly, or intraocularly.

In certain embodiments, the methods further comprise administration ofan additional agent. In certain embodiments, the additional agent is fortreatment of the primary tumor or the secondary tumor. In certainembodiments, the agent for treatment of the primary tumor or thesecondary tumor is a chemotherapeutic agent. In certain embodiments, thesubject is further treated with radiation therapy. In certainembodiments, the subject is further treated with surgery.

In certain embodiments, the subject is human.

In certain embodiments, CoQ10 compound is administered at a dose of atleast 50 mg/kg, at a dose of at least 75 mg/kg, at a dose of at least100 mg/kg, at a dose of at least 125 mg/kg, at a dose of at least 150mg/kg, at a dose of at least 200 mg/kg, at a dose of no more than 500mg/kg, at a dose of no more than 400 mg/kg, at a dose of no more than300 mg/kg.

In certain embodiments, the CoQ10 compound is administered three timesper week. In certain embodiments, the CoQ10 compound is administered atleast three times per week.

In certain embodiments, the CoQ10 compound is administered byintravenous infusion.

In certain embodiments, the CoQ10 compound is provided in an intravenousCoQ10 formulation comprising:

-   -   an aqueous solution;    -   a CoQ10 dispersed into a nano-dispersion of particles; and    -   at least one of a dispersion stabilizing agent and an        opsonization reducer;

wherein the nano-dispersion of the CoQ10 is dispersed intonano-particles having a mean particle size of less than 200-nm.

In certain embodiments, the dispersion stabilizing agent is selectedfrom the group consisting of pegylated castor oil, Cremophor EL,Cremophor RH 40, Pegylated vitamin E, Vitamin E TPGS, andDimyristoylphosphatidyl choline (DMPC). In certain embodiments, theopsonization reducer is selected from the group consisting of poloxamersand poloxamines, e.g., poloxamer 188. In certain embodiments, the CoQ10formulation has a weight-per-volume of the CoQ10, DMPC and poloxamer 188of 4%, 3% and 1.5%, respectively.

In certain embodiments, the CoQ10 compound is administered topically.

In certain embodiments, the CoQ10 compound for topical administration isa 3% CoQ10 cream comprising:

-   -   (1) a phase A having C12-15 alkyl benzoate at about 4.0% w/w of        the composition, cetyl alcohol at about 2.00% w/w of the        composition, stearyl alcohol at about 1.5% w/w, glyceryl        stearate and PEG-100 at about 4.5% w/w;    -   (2) a phase B having glycerin at about 2.00% w/w, propylene        glycol at about 1.5% w/w, ethoxydiglycol at about 5.0% w/w,        phenoxyethanol at about 0.475% w/w, a carbomer dispersion at        about 40% w/w, purified water at about 16.7% w/w;    -   (3) a phase C having triethanolamine at about 1.3% w/w, lactic        acid at about 0.5% w/w, sodium lactate solution at about 2.0%        w/w, water at about 2.5% w/w;    -   (4) a phase D having titanium dioxide at about 1.0% w/w; and    -   (5) a phase E having CoQ10 21% concentrate at about 15.0% w/w.

The invention provides compositions for practicing any of the methodsprovided herein.

The invention provides for the use of any of the compounds of claimsprovided herein for preparation of a medicament for use in the methodsprovided herein.

The invention provides composition for treating a central nervous system(CNS) tumor in a subject exhibiting at least one CNS abnormality thecomposition comprising a Coenzyme Q10 (CoQ10) compound, thereby treatingthe CNS tumor.

The invention provides compositions for preventing or treating of asecondary CNS tumor from a primary tumor in a subject the compositioncomprising a Coenzyme Q10 (CoQ10) compound, thereby preventing ortreating the secondary CNS tumor.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present disclosure will be described hereinbelow with reference to the figures wherein:

FIGS. 1A and B: Onset of paraplegia in Fischer 344 Rats. Development ofparaplegia following treatment for leukemia with lipopolysaccharide (A),and the same animal following treatment with CoQ10 (B).

FIG. 2: Mortality Curves for animals treated with or without CoQ10. Adecrease in mortality due to CNS tumors is observed in a dose-dependentmanner with CoQ10.

FIGS. 3A and B: MRI imaging of lesions depicting the chloroma in thespinal area before (A) and after CoQ10 treatment (B) in the same animal.

FIG. 4: Long-term Effect of CoQ10 on CNS Leukemia. 300 paraplegicanimals with overt CNS leukemia were randomized into two groups of 150animals each: one received phosphate buffered saline (PBS) and the othergroup received 100 mg/kg CoQ10 once daily starting on day 1 through day28 (first cycle). A second cycle of 100 mg/kg CoQ10 once daily startedon day 35 and continued through day 62. Animals received two cycles of28 days each of CoQ10. On days 173 and 195 as indicated by *, 5 animalswere sacrificed for necropsy and pathology analysis.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS I. Definitions

As used herein, a “central nervous system (CNS) tumor” is understood asa tumor present in at least one of the spinal cord, the brain, and theeye. The tumor may be a primary tumor, i.e. a tumor derived from a cellof the CNS. The tumor may be a metastatic tumor that originated at aremote site, i.e., a site outside of the CNS. A CNS tumor may alsometastasize from one site in the CNS to another site within the CNS,e.g., from brain to spine. A CNS tumor can include one or more of aneuroepithelial tissue tumor, a tumor of cranial and/or paraspinalnerves, a tumor of the meninges, a tumor of the haematopoietic system, agerm cell tumor, a tumor of the sellar region, a lymphoma, a leukemia, amelanoma, a carcinoma, and a sarcoma tumor. Leukemic tumors include, forexample, chloroleukemic tumors, acute lymphoblastic leukemia (ALL)tumors, acute myelogenous leukemia (AML) tumors, acute promyelogenousleukemia tumors, and mixed lineage leukemia tumors.

The terms “cancer” or “tumor” are well known in the art and refer to thepresence, e.g., in a subject, of cells possessing characteristicstypical of cancer-causing cells, such as uncontrolled proliferation,immortality, metastatic potential, rapid growth and proliferation rate,decreased cell death/apoptosis, and certain characteristic morphologicalfeatures. As used herein, the term “cancer” includes pre-malignant aswell as malignant cancers.

As used herein, “cancer” refers to all types of cancer or neoplasm ormalignant tumors found in humans, including, but not limited to:leukemias, lymphomas, melanomas, carcinomas and sarcomas. As usedherein, the terms or language “cancer,” “neoplasm,” and “tumor,” areused interchangeably and in either the singular or plural form, refer tocells that have undergone a malignant transformation that makes thempathological to the host organism. Primary cancer cells (that is, cellsobtained from near the site of malignant transformation) can be readilydistinguished from non-cancerous cells by well-established techniques,particularly histological examination. The definition of a cancer cell,as used herein, includes not only a primary cancer cell, but also cancerstem cells, as well as cancer progenitor cells or any cell derived froma cancer cell ancestor. This includes metastasized cancer cells, and invitro cultures and cell lines derived from cancer cells. When referringto a type of cancer that normally manifests as a solid tumor, a“clinically detectable” tumor is one that is detectable on the basis oftumor mass; e.g., by procedures such as CAT scan, MR imaging, X-ray,ultrasound or palpation, and/or which is detectable because of theexpression of one or more cancer-specific antigens in a sampleobtainable from a patient.

As used herein, a “pediatric tumor” or “pediatric cancer” is a tumor orcancer first identified in a subject at or before the age of 18.Pediatric tumors include, but are not limited to, Ewing sarcoma,leukemia, neuroblastoma, osteosarcoma, rhabdomyosarcoma, soft tissuesarcoma, and Wilms' tumor.

A “central nervous system (CNS) abnormality” is understood as a sign orsymptom of the presence of a CNS tumor that results in a change inbehavior or physical well being of a subject as a result of the presenceof the tumor. A subject may experience one or more CNS abnormalities asa result of a CNS tumor. The specific CNS abnormality will typicallydepend on, at least in part, the location, size, and type of CNS tumor.CNS abnormalities include, but are not limited to, headache, a seizure,a change in memory especially loss of short term memory, a change intemperament, e.g., sudden onset of panic attacks induced by familiarsituations, a change in intellectual function, e.g., inability to domath or find objects in plain sight; confusion, disorientation, e.g.,becoming lost in a familiar location; blurred vision, loss of vision,loss of peripheral vision, double vision, dizziness, hearing problems,ringing in ears, buzzing in ears, seizure, decreased muscle control,lack of coordination, decreased sensation, weakness, paralysis, e.g.,paraplegia, quadriplegia, difficulty with walking or change in gait,difficulty with speech, and balance problems. As used herein, the CNSabnormality may be reported by anyone observing the subject, eitherdirectly or indirectly, e.g., the subject with the CNS abnormality himor herself, by a companion or caregiver of the subject with the CNSabnormality, or one of skill in the art. A CNS abnormality can include aphysical abnormality detected by palpation or observed in an imagingstudy, e.g., by procedures such as CAT scan, MR imaging, X-ray,ultrasound, including an imaging study performed for a reason other thanto detect the CNS abnormality. The CNS abnormalities need not bequantitatively or qualitatively analyzed as compared to a time prior todevelopment of the CNS abnormality. As used herein, the CNS abnormalitymay be recognized by the subject prior to seeking treatment. In certainembodiments, the CNS abnormality is recognized after diagnosis of a CNStumor by other methods (e.g., imaging study performed for reasons otherthan a CNS abnormality). In certain embodiments, the CNS tumor isdetected when the subject seeks treatment for the CNS abnormality.

As used herein, the terms “treat,” “treating” or “treatment” refer,preferably, to an action to obtain a beneficial or desired clinicalresult including, but not limited to, alleviation or amelioration of oneor more signs or symptoms of a disease or condition, diminishing theextent of disease, stability (i.e., not worsening) state of disease,amelioration or palliation of the disease state, diminishing rate of ortime to progression, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” of a cancer can also meanprolonging survival as compared to expected survival in the absence oftreatment. Treatment need not be curative.

As used herein, “prevention of a secondary CNS tumor” is understood asdelaying the onset, limiting the severity, or reducing the incidence ofthe development of a secondary CNS tumor in a subject suffering from orin a subject that has been treated for cancer, e.g., by prevention ofextravasation of cancer cells into the CNS. In certain embodiments, thecancer is a leukemia, e.g., a chloroleukemia. In certain embodiment, thetumor is a pediatric tumor. The time to incidence and frequency of tumormetastasis to the CNS for various tumor types are known in the art.

As used herein, “amelioration of at least one CNS abnormality” isunderstood as the lessening in severity or frequency of one or more(e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) CNS abnormalityexperienced by the subject as a result of treatment of the CNS tumor.Amelioration of at least one CNS abnormality can be understood asamelioration of 1-10, 2-10, 3-10, 4-10, 5-15, or more CNS abnormalities.Amelioration need not include complete elimination of signs or symptomsof the abnormality.

“Chemotherapeutic agent” is understood as a drug used for the treatmentof cancer. Chemotherapeutic agents include, but are not limited to,small molecules and biologics (e.g., antibodies, peptide drugs, nucleicacid drugs).

A “therapeutically effective amount” is that amount sufficient to treata disease in a subject. A therapeutically effective amount can beadministered in one or more administrations.

The terms “administer”, “administering” or “administration” include anymethod of delivery of a pharmaceutical composition or agent into asubject's system or to a particular region in or on a subject. Incertain embodiments, the agent is delivered orally. In certainembodiments, the agent is administered parenterally. In certainembodiments, the agent is delivered by injection or infusion. In certainembodiments, the agent is delivered topically including transmucosally.In certain embodiments of the invention, an agent is administered byparenteral delivery, including, intravenous, intramuscular,subcutaneous, intramedullary injections, as well as intrathecal, directintraventricular, intraperitoneal, intranasal, or intraocularinjections. In one embodiment, the compositions provided herein may beadministered by injecting directly to a tumor. In some embodiments, theformulations of the invention may be administered by intravenousinjection or intravenous infusion. In certain embodiments,administration is systemic. In certain embodiments, administration islocal. In some embodiments, one or more routes of administration may becombined, such as, for example, intravenous and intratumoral, orintravenous and peroral, or intravenous and oral, intravenous andtopical, or intravenous and transdermal or transmucosal. In certainembodiments, the agent is not administered directly to the CNS, e.g.,the agent is not delivered intrathecally, intratumorally,intracranially, intraventricularly, intramedullaryly, or intraocularly.Administering an agent can be performed by a number of people working inconcert. Administering an agent includes, for example, prescribing anagent to be administered to a subject and/or providing instructions,directly or through another, to take a specific agent, either byself-delivery, e.g., as by oral delivery, subcutaneous delivery,intravenous delivery through a central line, etc.; or for delivery by atrained professional, e.g., intravenous delivery, intramusculardelivery, intratumoral delivery, etc.

As used herein, a “pharmaceutically acceptable” component is one that issuitable for use with humans and/or animals without undue adverse sideeffects (such as toxicity, irritation, and allergic response)commensurate with a reasonable benefit/risk ratio.

As used herein, a “formulation” is understood as an active ingredient,e.g., CoQ10, a metabolite of CoQ10, a biosynthetic precursor of CoQ10,or a CoQ10 related compound, in combination with any pharmaceuticallyacceptable carrier. Formulations can include, but are not limited to,aqueous formulations, liposomal formulations, suspensions, emulsions,microemulsions, formulations for specific routes of administration, suchas cream, lotion, and ointment formulations for topical administration,and solid formulations for oral administration.

As used herein, the term “safe and therapeutic effective amount” refersto the quantity of a component which is sufficient to yield a desiredtherapeutic response without undue adverse side effects (such astoxicity, irritation, or allergic response) commensurate with areasonable benefit/risk ratio when used in the manner of thisdisclosure. By “therapeutically effective amount” is meant an amount ofa compound of the present disclosure effective to yield the desiredtherapeutic response, e.g., amelioration of at least one sign or symptomof CNS tumor including amelioration of at least one CNS abnormality. Thespecific safe and effective amount or therapeutically effective amountwill vary with such factors as the particular condition being treated,the physical condition of the patient, the type of mammal or animalbeing treated, the duration of the treatment, the nature of concurrenttherapy (if any), and the specific formulations employed and thestructure of the compounds or its derivatives.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. When administered for preventinga disease, the amount is sufficient to avoid or delay onset of thedisease. The “therapeutically effective amount” will vary depending onthe compound, the disease and its severity and the age, weight, etc., ofthe patient to be treated.

The term “therapeutic effect” refers to a local or systemic effect inanimals, particularly mammals, and more particularly humans caused by apharmacologically active substance. The term thus means any substanceintended for use in the diagnosis, cure, mitigation, treatment orprevention of disease or in the enhancement of desirable physical ormental development and conditions in an animal or human. The phrase“therapeutically-effective amount” means that amount of such a substancethat produces some desired local or systemic effect at a reasonablebenefit/risk ratio applicable to any treatment. In certain embodiments,a therapeutically-effective amount of a compound will depend on itstherapeutic index, solubility, and the like. For example, certaincompounds discovered by the methods of the present invention may beadministered in a sufficient amount to produce a reasonable benefit/riskratio applicable to such treatment.

As used herein, “co-administration” or “combination therapy” isunderstood as administration of two or more active agents using separateformulations or a single pharmaceutical formulation, or consecutiveadministration in any order such that, there is a time period while both(or all) active agents simultaneously exert their biological activities.Co-administration does not require that the agents are administered atthe same time, at the same frequency, or by the same route ofadministration. Examples of chemotherapeutic agents are provided herein.

As used herein, “co-administration” or “combination therapy” includesadministration of a CoQ10 compound with one or more chemotherapeuticagent, or administration of two or more CoQ10 compounds.

As used herein, the term “survival” refers to the continuation of lifeof a subject which has been treated for a disease or condition, e.g.,cancer. The time of survival can be defined from an arbitrary point suchas time of entry into a clinical trial, time from completion or failureor an earlier treatment regimen, time from diagnosis, etc.

As used herein, the term “subject” refers to human and non-humananimals, including veterinary subjects. The term “non-human animal”includes all vertebrates, e.g., mammals and non-mammals, such asnon-human primates, mice, rabbits, sheep, dog, cat, horse, cow,chickens, amphibians, and reptiles. In a preferred embodiment, thesubject is a human and may be referred to as a patient.

The articles “a”, “an” and “the” are used herein to refer to one or tomore than one (i.e. to at least one) of the grammatical object of thearticle unless otherwise clearly indicated by contrast. By way ofexample, “an element” means one element or more than one element.

The term “including” is used herein to mean, and is used interchangeablywith, the phrase “including but not limited to”.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or,” unless context clearly indicates otherwise.

The term “such as” is used herein to mean, and is used interchangeably,with the phrase “such as but not limited to”.

Unless specifically stated or obvious from context, as used herein, theterm “about” is understood as within a range of normal tolerance in theart, for example within 2 standard deviations of the mean. About can beunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear fromcontext, all numerical values provided herein can be modified by theterm about.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

The recitation of a listing of chemical group(s) in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable or aspect herein includes that embodiment as any singleembodiment or in combination with any other embodiments or portionsthereof.

Any compositions or methods provided herein can be combined with one ormore of any of the other compositions and methods provided herein.

II. Coenzyme Q10 Compounds

CoEnzyme Q10 compounds are intended to include a class of CoQ10compounds. Coenzyme Q10 compounds effective for the methods describedherein include CoQ10, a metabolite of CoQ10, a biosynthetic precursor ofCoQ10, an analog of CoQ10, a derivative of CoQ10, and CoQ10 relatedcompounds. An analog of CoQ10 includes analogs having no or at least oneisoprenyl repeats. CoQ10 has the following structure:

wherein x is 10. In the instant invention, CoQ10 can include derivativesof CoQ10 in which x is any number of isoprenyl units from 4-10, or anynumber of isoprenyl units from 6-10, or any number of isoprenyl unitsfrom 8-10, or 9-10 isoprenyl units. CoQ10 includes the fully oxidizedversion, also known as ubiquinone, the partially oxidized version, alsoknown as semiquinone or ubisemiquinone, or the fully reduced version,also known as ubiquinol; or any mixtures or combinations thereof. Incertain embodiments, the agent for treatment of a CNS tumor isubiquinone. In certain embodiments, the agent for treatment of a CNStumor is ubiquinols.

In certain embodiments of the present invention, the therapeutic agentis Coenzyme Q10 (CoQ10). Coenzyme Q10, also referred to herein as CoQ10,is also known as ubiquinone, or ubidecarenone. CoQ10 is art-recognizedand further described in International Publication No. WO 2005/069916,the entire disclosure of which is incorporated by reference herein.CoQ10 is one of a series of polyprenyl2,3-dimethoxy-5-methylbenzoquinone (ubiquinone) present in themitochondrial electron transport systems of eukaryotic cells. Humancells produce CoQ10 exclusively and it is found in cell andmitochondrial membranes of all human cells, with the highest levels inorgans with high energy requirements, such as the liver and the heart.The body pool of CoQ10 has been estimated to be about 2 grams, of whichmore than 50% is endogenous. Approximately 0.5 grams of CoQ10 isrequired from the diet or biosynthesis each day. CoQ10 is produced inton quantities from the worldwide supplement market and can be obtainedfrom Kaneka, with plants in Pasadena, Tex. and Takasagoshi, Japan.

Coenzyme Q10 related compounds include, but are not limited to,benzoquinones, isoprenoids, farnesols, farnesyl acetate, farnesylpyrophosphate, 1-phenylalanine, d-phenylalanine, dl-phenylalanine,1-tyrosine, d-tyrosine, dl-tyrosine, 4-hydroxy-phenylpyruvate,4-hydroxy-phenyllactate, 4-hydroxy-cinnamate, dipeptides and tripeptidesof tyrosine or phenylalanine, 3,4-dihydroxymandelate, 3-methoxy-4-hydroxyphenylglycol, 3-methoxy-4-hydroxymandelate, vanillicacid, phenylacetate, pyridoxine, S-adenosyl methionine, panthenol,mevalonic acid, isopentyl pyrophosphate, phenylbutyrate,4-hydroxy-benzoate, decaprenyl pyrophosphate, beta-hydroxybutyrate,3-hydroxy-3-methyl-glutarate, acetylcarnitine, acetoacetylcarnitine,acetylglycine, acetoacetylglycine, carnitine, acetic acid, pyruvic acid,3-hydroxy-3-methylglutarylcarnitine, all isomeric forms of serine,alanine, cysteine, glycine, threonine, hydroxyproline, lysine,isoleucine, and leucine, even carbon number C4 to C8 fatty acids(butyric, caproic, caprylic, capric, lauric, myristic, palmitic, andstearic acids) salts of carnitine and glycine, e.g., palmitoylcarnitineand palmitoylglycine, and 4-hydroxy-benzoate polyprenyltransferase, anysalts of these compounds, as well as any combinations thereof, and thelike. In certain embodiments, such agents can be used for the treatmentof a CNS tumor.

Metabolites and biosynthetic precursors of CoQ10 include, but are notlimited to, those compounds that are formed between thechemical/biological conversion of tyrosine and acetyl-CoA to ubiquinol.Intermediates of the coenzyme biosynthesis pathway include tyrosine,acetyl-CoA, 3-hexaprenyl-4-hydroxybenzoate,3-hexaprenyl-4,5-dihydroxybenzoate,3-hexaprenyl-4-hydroxy-5-methoxybenzoate,2-hexaprenyl-6-methoxy-1,4-benzoquinone,2-hexaprenyl-3-methyl-6-methoxy-1,4-benzoquinone,2-hexaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone,3-Octaprenyl-4-hydroxybenzoate, 2-octaprenylphenol,2-octaprenyl-6-metholxyphenol,2-octaprenyl-3-methyl-6-methoxy-1,4-benzoquinone,2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone,2-decaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone,2-decaprenyl-3-methyl-6-methoxy-1,4-benzoquinone,2-decaprenyl-6-methoxy-1,4-benzoquinone, 2-decaprenyl-6-methoxyphenol,3-decaprenyl-4-hydroxy-5-methoxybenzoate,3-decaprenyl-4,5-dihydroxybenzoate, 3-decaprenyl-4-hydroxybenzoate,4-hydroxy phenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxy-benzoate,4-hydroxycinnamate, and hexaprenydiphosphate. In certain embodiments,such agents can be used for the treatment of a CNS tumor.

III. Compositions

The present disclosure provides compositions containing a CoQ10 compoundfor the treatment and prevention of cancer. The composition of thepresent disclosure can be administered to a patient either bythemselves, or in pharmaceutical compositions where it is mixed withsuitable carriers or excipient(s). In treating a patient exhibiting adisorder of interest, a therapeutically effective amount of an agent oragents such as these is administered. A therapeutically effective doserefers to that amount of the compound which results in amelioration ofsymptoms or a prolongation of survival in a patient.

Suitable routes of administration of the present compositions of theinvention may include parenteral delivery, including, intravenous,intramuscular, subcutaneous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections, just to name a few. In one embodiment, thecompositions provided herein may be administered by injecting directlyto a tumor. In some embodiments, the formulations of the invention maybe administered by intravenous injection or intravenous infusion. In oneembodiment, the compositions of the invention are administered byintravenous injection. In one embodiment, the compositions of theinvention are administered by intravenous infusion. Where the route ofadministration is, for example intravenous infusion, embodiments areprovided herein where the IV infusion comprises the active agent, e.g.,CoQ10, at approximately a 40 mg/mL concentration. Where the compositionis administered by IV infusion, it can be diluted in a pharmaceuticallyacceptable aqueous solution such as phosphate buffered saline or normalsaline. In some embodiments, one or more routes of administration may becombined, such as, for example, intravenous and intratumoral, orintravenous and peroral, or intravenous and oral, or intravenous andtopical, transdermal, or transmucosal.

The compositions described herein may be administered to a subject inany suitable formulation. These include, for example, liquid,semi-solid, and solid dosage forms, such as liquid solutions (e.g.,injectable and infusible solutions), dispersions or suspensions,tablets, pills, powders, creams, lotions, liniments, ointments, orpastes, drops for administration to the eye, ear or nose, liposomes, andsuppositories. The preferred form depends on the intended mode ofadministration and therapeutic application.

In certain embodiments, a CoQ10 compound may be prepared with a carrierthat will protect against rapid release, such as a controlled releaseformulation, including implants, transdermal patches, andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Manymethods for the preparation of such formulations are patented orgenerally known to those skilled in the art. See, e.g., Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978.

For example, a CoQ10 compound can be formulated for parenteral delivery,e.g., for subcutaneous, intravenous, intramuscular, or intratumoralinjection. The compositions may be administered in a single bolus,multiple injections, or by continuous infusion (for example,intravenously or by peritoneal dialysis). For parenteral administration,the compositions may be formulated in a sterilized pyrogen-free form.

Use of pharmaceutically acceptable carriers to formulate the compoundsherein disclosed, for the practice of the present invention, intodosages suitable for systemic administration is within the scope of thepresent disclosure. With proper choice of carrier and suitablemanufacturing practice, the compositions of the present disclosure, inparticular, those formulated as solutions, may be administeredparenterally, such as by intravenous injection.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED50 (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD50/ED50.Compounds which exhibit large therapeutic indices may be desirable. Thedata obtained from these cell culture assays and animal studies can beused in formulating a range of dosage for use in human. The dosage ofsuch compounds may be within a range of circulating concentrations thatinclude the ED50 with little or no toxicity. The dosage may vary withinthis range depending upon the dosage form employed and the route ofadministration utilized.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. Determination of theeffective amounts is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein. Inaddition to the active ingredients, these pharmaceutical compositionsmay contain suitable pharmaceutically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Thepreparations formulated for intravenous administration may be in theform of solutions of colloidal dispersion.

Pharmaceutical compositions for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

IV. Formulations

The active agent, e.g., a CoQ10 compound, can be delivered in anypharmaceutically acceptable carrier for the desired route ofadministration. As used herein, formulations including CoQ10 compoundsare formulated for any route of administration unless otherwise clearlyindicated. In preferred embodiments, the formulations are foradministration by injection, infusion, or topical administration.

Preferred therapeutic formulations for use in the methods of theinvention comprise the active agent (e.g., a CoQ10 compound) in amicroparticle formation, e.g., for intravenous administration. Suchintravenous formulations are provided, for example, in WO2011/112900which is incorporated herein in its entirety by reference and anintravenous formulation is used in the examples set forth below. Throughhigh pressure homogenization, active agent (e.g., a CoQ10 compound)particles are reduced to produce particles that are small enough to passthrough a 200-nm sterilizing filter. Particles that are small enough topass through a 200-nm sterilizing filter can be injected intravenously.These particles are much smaller than blood cells and therefore will notembolize capillaries. Red blood cells for example are 6-micron×2-microndisks. The particles are dispersed to and are encased or surrounded by astabilizing agent. While not wishing to be bound by any theory, it isbelieved that the stabilizing agents are attracted to the hydrophobictherapeutic agent such that the dispersed particles of the hydrophobictherapeutic agent are surrounded by the stabilizing agent forming asuspension or an emulsion. The dispersed particles in the suspension oremulsion comprises a stabilizing agent surface and a core consisting ofthe hydrophobic therapeutic agent, e.g., a CoQ10 compound, in a solidparticulate form (suspension) or in an immiscible liquid form(emulsion). The dispersed particles can be entrenched in the lipophilicregions of a liposome.

Dispersed colloidal systems permit a high drug load in the formulationwithout the use of co-solvents. Additionally, high and relativelyreproducible plasma levels are achieved without the dependence onendogenous low-density lipoprotein carriers. More importantly, theformulations allow sustained high drug levels in solid tumors due to thepassive accumulation of the colloidal particles of the hydrophobictherapeutic agent.

A preferred intravenous formulation substantially comprises a continuousphase of water and dispersed solids (suspension) or dispersed immiscibleliquid (emulsion). Dispersed colloidal systems, in which the particlesare composed largely of the active agent (drug) itself, can oftendeliver more drug per unit volume than continuous solubilizing systems,if the system can be made adequately stable.

As the formulation medium, the aqueous solution may include Hank'ssolution, ringer's solution, phosphate buffered saline (PBS),physiological saline buffer or other suitable salts or combinations toachieve the appropriate pH and osmolarity for parenterally deliveredformulations. The aqueous solution may contain substances which increasethe viscosity of the solution, such as sodium carboxymethyl cellulose,sorbitol, or dextran.

The active agent (e.g., a CoQ10 compound) is dispersed in the aqueoussolution such that a colloidal dispersion is formed wherein thenano-dispersion particles of the hydrophobic therapeutic agent arecovered or encased or encircled by the dispersion stabilizing agents toform nano-dispersions of the active agent (e.g., a CoQ10 compound)particles. The nano-dispersed active agent (e.g., a CoQ10 compound)particles have a core formed of the hydrophobic therapeutic agent thatis surrounded by the stabilizing agent. Similarly, in certain aspects,the stabilizing agent is a phospholipid having both a hydrophilic andlipophilic portion. The phospholipids form liposomes or othernanoparticles upon homogenization. In certain aspects these liposomesare bi-layered unilamellar liposomes while in other embodiments theliposomes are bi-layered multi-lamellar liposomes. The dispersed activeagent (e.g., a CoQ10 compound) particles are dispersed in the lipophilicportion of the bi-layered structure of the liposome formed from thephospholipids. In certain other aspects the core of the liposome, likethe core of the nano-dispersion of active agent (e.g., a CoQ10 compound)particles, is formed of the hydrophobic therapeutic agent and the outerlayer is formed of the bi-layered structure of the phospholipid. Incertain embodiments the colloidal dispersions are treated by alyophilization process whereby the nanoparticle dispersion is convertedto a dry powder.

In some embodiments, the formulation for injection or infusion used is a4% sterile aqueous colloidal dispersion containing CoQ10 in ananosuspension as prepared in WO2011/112900. In certain embodiments, theformulation includes an aqueous solution; a hydrophobic active agent,e.g., CoQ10, a CoQ10 precursor or metabolite or a CoQ10 relatedcompound, dispersed to form a colloidal nano-dispersion of particles;and at least one of a dispersion stabilizing agent and an opsonizationreducer; wherein the colloidal nano-dispersion of the active agent isdispersed into nano-dispersion particles having a mean size of less than200-nm.

In certain embodiments, the dispersion stabilizing agent includes, butis not limited to, pegylated castor oil, Cremphor EL, Cremophor RH 40,Pegylated vitamin E, Vitamin E TPGS, and Dimyristoylphosphatidyl choline(DMPC).

In certain embodiments, the opsonization reducer is a poloxamer or apoloxamines.

In certain embodiments, the colloidal nano-dispersion is a suspension oran emulsion, optionally, a colloidal nano-dispersion is in a crystallineform or a super-cooled melt form.

In certain embodiments, the formulation includes a lyoprotectant such asa nutritive sugar including, but not limited to, lactose, mannose,maltose, galactose, fructose, sorbose, raffinose, neuraminic acid,glucosamine, galactosamine, N-methylglucosamine, mannitol, sorbitol,arginine, glycine and sucrose, or any combination thereof.

In certain embodiments, the injectable formulation includes an aqueoussolution; a hydrophobic active agent dispersed to form a colloidalnano-dispersion of particles; and at least one of a dispersionstabilizing agent and an opsonization reducer. The colloidalnano-dispersion of the active agent is dispersed into nano-dispersionparticles having sizes of less than 200-nm. In some embodiments thedispersion stabilizing agent is selected from natural or semisyntheticphospholipids. For example, suitable stabilizing agents includepolyethoxylated (a/k/a pegylated) castor oil (Cremophor® EL),polyethoxylated hydrogenated castor oil (Cremophor® RH 40), Tocopherolpolyethylene glycol succinate (Pegylated vitamin E, Vitamin E TPGS),Sorbitan fatty acid esters (Spans®), Bile acids and bile-acid salts orDimyristoylphosphatidyl choline (DMPC). In some embodiments thestabilizing agent is DMPC.

In certain embodiments the formulation is suitable for parenteraladministration, including intravenous, intraperitoneal, orthotopical,intracranial, intramuscular, subcutaneous, intramedullary injections, aswell as intrathecal, direct intraventricular, intranasal, or intraocularinjections. In certain embodiments, the formulation contains CoQ10,dimyristoyl-phophatidylcholine, and poloxamer 188 in a ratio of 4:3:1.5respectively that is designed to stabilize the nanosuspension of theparticles. In some embodiments, the formulation includes a phosphatebuffer saline solution which contains sodium phosphate dibasic,potassium phosphate monobasic, potassium chloride, sodium chloride andwater for injection. In certain embodiments, the 4% sterile aqueouscolloidal dispersion containing CoQ10 in a nanosuspension is diluted inthe phosphate buffered saline solution provided, e.g., 1:1, 1:2, 1:3,1:4. 1:5, 1:6, 1:7, 1:8. 1:9, 1:10, 1:11, 1:12, 1:13, 1:14. 1:15, 1:16,1:17, 1:18. 1:19, 1:20, or other appropriate ratio bracketed by any twoof the values.

In some embodiments, the formulation is a topical formulation. Topicalformulations of CoQ10 compounds are provided, for example inWO2010/132507, WO2009/126764, WO2008116135, and WO2005/069916, theentire contents of each are expressly incorporated herein.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin, suchas liniments, lotions, creams, ointments or pastes, and drops suitablefor administration to the eye, ear, or nose. Drops according to thepresent disclosure may include sterile aqueous or oily solutions orsuspensions and may be prepared by dissolving the active ingredient in asuitable aqueous solution of a bactericidal and/or fungicidal agentand/or any other suitable preservative, and in some embodimentsincluding a surface active agent. The resulting solution may then beclarified and sterilized by filtration and transferred to the containerby an aseptic technique. Examples of bactericidal and fungicidal agentssuitable for inclusion in the drops are phenylmercuric nitrate oracetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidineacetate (0.01%). Suitable solvents for the preparation of an oilysolution include glycerol, diluted alcohol and propylene glycol.

Lotions according to the present disclosure include those suitable forapplication to the skin or eye. An eye lotion may include a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol, and/or amoisturizer such as glycerol or an oil such as castor oil or arachisoil.

Creams, ointments or pastes useful in the methods of the invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy basis. The basis may include hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives, or a fattyacid such as stearic or oleic acid together with an alcohol such aspropylene glycol or macrogels. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurface active such as sorbitan esters or polyoxyethylene derivativesthereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

In some embodiments, the remaining component of a topical deliveryvehicle may be water or a water phase, in embodiments purified, e.g.deionized, water, glycerine, propylene glycol, ethoxydiglycol,phenoxyethanol, and cross linked acrylic acid polymers. Such deliveryvehicle compositions may contain water or a water phase in an amount offrom about 50 to about 95 percent, based on the total weight of thecomposition. The specific amount of water present is not critical,however, being adjustable to obtain the desired viscosity (usually about50 cps to about 10,000 cps) and/or concentration of the othercomponents. The topical delivery vehicle may have a viscosity of atleast about 30 centipoises.

Topical formulations can also include an oil phase including, forexample, oil phase which, in turn, may include emollients, fattyalcohols, emulsifiers, combinations thereof, and the like. For example,an oil phase could include emollients such as C12-15 alkyl benzoates(commercially available as FINSOLV™ TN from Finetex Inc. (Edison,N.J.)), capric-caprylic triglycerides (commercially available from Hulsas MIGLYOL™ 812), and the like. Other suitable emollients which may beutilized include vegetable derived oils (corn oil, safflower oil, oliveoil, macadamian nut oil, etc.); various synthetic esters, includingcaprates, linoleates, dilinoleates, isostearates, fumarates, sebacates,lactates, citrates, stearates, palmitates, and the like; syntheticmedium chain triglycerides, silicone oils or polymers; fatty alcoholssuch as cetyl alcohol, stearyl alcohol, cetearyl alcohol, laurylalcohol, combinations thereof, and the like; and emulsifiers includingglyceryl stearate, PEG-100 stearate, Glyceryl Stearate, GlycerylStearate SE, neutralized or partially neutralized fatty acids, includingstearic, palmitic, oleic, and the like; vegetable oil extractscontaining fatty acids, Ceteareth-20, Ceteth-20, PEG-150 Stearate, PEG-8Laurate, PEG-8 Oleate, PEG-8 Stearate, PEG-20 Stearate, PEG-40 Stearate,PEG-150 Distearate, PEG-8 Distearate, combinations thereof, and thelike; or other non-polar cosmetic or pharmaceutically acceptablematerials used for skin emolliency within the purview of those skilledin the art, combinations thereof, and the like.

Topical formulations can also include a liposomal concentrate including,for example, a phospholipid such as lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol,phosphatidylglycerol, phosphatidic acid, phosphatidylserine,lysophosphatidylcholine, lysophosphatidylethanolamine,lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine,PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, andcombinations thereof, at least one lipophilic bioactive agent, and atleast one solubilizer. The liposomal concentrate may be in combinationwith at least one pharmaceutically acceptable carrier possessing atleast one permeation enhancer in an amount from about 0.5% by weight toabout 20% by weight of the composition. The phospholipid may present inthe composition in an amount from about 2% to about 20% by weight of thecomposition and the bioactive agent may be present in an amount fromabout 0.5% to about 20% by weight of the composition.

Transdermal skin penetration enhancers can also be used to facilitatedelivery of CoQ10. Illustrative are sulfoxides such as ethoxydiglycol,1,3-butylene glycol, isopentyl diol, 1,2-pentane diol, propylene glycol,2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate,hexan-2,5-diol, di(2-hydroxypropyl)ether, pentan-2,4-diol, acetone,polyoxyethylene(2)methyl ether, 2-hydroxypropionic acid,2-hydroxyoctanoic acid, propan-1-ol, 1,4 dioxane, tetrahydrofuran,butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol,oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate,diisopropyl adipate, diisopropyl sebacate, dibutyl sebacate, diethylsebacate, dimethyl sebacate, dioctyl sebacate, dibuyl suberate, dioctylazelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethylmyristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecylphthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropylpalmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropylisostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyllaurate, ethyl caprate, ethyl caprylate, butyl stearate, benzylsalicylate, 2-hyroxyoctanoic acid, dimethyl sulphoxide, methyl sufonylmethane, n,n-dimethyl acetamide, n,n-dimethyl formamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone,1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides,sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide,1-dodecylazacyloheptan-2-one, and combinations thereof.

Solubilizers, particularly for topical administration can include, butare not limited to, polyoxyalkylene dextrans, fatty acid esters ofsaccharose, fatty alcohol ethers of oligoglucosides, fatty acid estersof glycerol, fatty acid esters of polyoxyethylenes, polyethoxylatedfatty acid esters of sorbitan, fatty acid esters of poly(ethyleneoxide), fatty alcohol ethers of poly(ethylene oxide), alkylphenol ethersof poly(ethylene oxide), polyoxyethylene-polyoxypropylene blockcopolymers, ethoxylated oils, and combinations thereof.

Topical formulations can include emollients, including, but not limitedto, C12-15 alkyl benzoates, capric-caprylic triglycerides, vegetablederived oils, caprates, linoleates, dilinoleates, isostearates,fumarates, sebacates, lactates, citrates, stearates, palmitates,synthetic medium chain triglycerides, silicone oils, polymers andcombinations thereof; the fatty alcohol is selected from the groupconsisting of cetyl alcohol, stearyl alcohol, cetearyl alcohol, laurylalcohol and combinations thereof; and the emulsifier is selected fromthe group consisting of glyceryl stearate, polyethylene glycol 100stearate, neutralized fatty acids, partially neutralized fatty acids,polyethylene glycol 150 stearate, polyethylene glycol 8 laurate,polyethylene glycol oleate, polyethylene glycol 8 stearate, polyethyleneglycol 20 stearate, polyethylene glycol 40 stearate, polyethylene glycol150 distearate, polyethylene glycol 8 distearate, and combinationsthereof.

Topical formulations can include a neutralization phase comprising oneor more of water, amines, sodium lactate, and lactic acid.

The water phase can further optionally include one or more of waterphase comprises the permeation enhancer optionally in combination with aviscosity modifier selected from the group consisting of cross linkedacrylic acid polymers, pullulan, mannan, scleroglucans,polyvinylpyrrolidone, polyvinyl alcohol, guar gum, hydroxypropyl guargum, xanthan gum, acacia gum, arabia gum, tragacanth, galactan, carobgum, karaya gum, locust bean gum, carrageenin, pectin, amylopectin,agar, quince seed, rice starch, corn starch, potato starch, wheatstarch, algae extract, dextran, succinoglucan, carboxymethyl starch,methylhydroxypropyl starch, sodium alginate, alginic acid propyleneglycol esters, sodium polyacrylate, polyethylacrylate, polyacrylamide,polyethyleneimine, bentonite, aluminum magnesium silicate, laponite,hectonite, and anhydrous silicic acid.

Topical formulations can also include a pigment such as titaniumdioxide.

In an embodiment, a topical formulation for use in the methods of theinvention includes an oil phase comprising C12-15 alkyl benzoates, cetylalcohol, stearyl alcohol, glyceryl stearate, and polyethylene glycol 100stearate, in an amount of from about 5% to about 20% by weight of thecomposition; a water phase comprising glycerin, propylene glycol,ethoxydiglycol, phenoxyethanol, water, and a crosslinked acrylic acidpolymer, in an amount of from about 60 to about 80% by weight of thecomposition; a neutralization phase comprising water, triethanolamine,sodium lactate, and lactic acid, in an amount of from about 0.1% toabout 15% by weight of the composition; a pigment comprising titaniumdioxide in an amount of from about 0.2% to about 2% by weight of thecomposition; and a liposomal concentrate comprising a polyethoxylatedfatty acid ester of sorbitan, coenzyme Q10, a phosphatidylcholinelecithin, phenoxyethanol, propylene glycol, and water, in an amount offrom about 0.1% to about 30% by weight of the composition, wherein thepropylene glycol and ethoxydiglycol are present in a combined amount offrom 3% by weight to about 15% by weight of the composition and thecoenzyme Q10 is present in an amount of from about 0.75% by weight toabout 10% by weight of the composition. Other formulations for use inthe methods of the invention are provided, for example, in WO2008/116135which is incorporated herein by reference.

In some embodiments, a formulation for any route of administration foruse in the invention may include from about 0.001% to about 20% (w/w) ofCoQ10, more preferably between about 0.01% and about 15% and even morepreferably between about 0.1% to about 10% (w/w) of CoQ10. In oneembodiment a formulation includes about 4% (w/w) of CoQ10. In oneembodiment a formulation includes about 8% (w/w) of CoQ10. In variousembodiments, the formulation includes about 0.1%, 0.2%, 0.3%, 0.4%,0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,16%, 17%, 18%, 19% or 20% (w/w) of CoQ10, or any range bracketed by anytwo values recited. CoQ10 can be obtained from Kaneka Q10 as Kaneka Q10(USP UBIDECARENONE) in powdered form (Pasadena, Tex., USA). CoQ10 usedin the methods exemplified herein have the following characteristics:residual solvents meet USP 467 requirement; water content is less than0.0%, less than 0.05% or less than 0.2%; residue on ignition is 0.0%,less than 0.05%, or less than 0.2% less than; heavy metal content isless than 0.002%, or less than 0.001%; purity of between 98-100% or99.9%, or 99.5%.

In certain embodiments, the concentration of CoQ10 in the formulation isbetween 1 mg/mL and 150 mg/mL. In one embodiment, the concentration ofCoQ10 in the formulation is between 5 mg/mL and 125 mg/mL. In oneembodiment, the concentration of CoQ10 in the formulation is between 10mg/mL and 100 mg/mL. In one embodiment, the concentration of CoQ10 inthe formulation is between 20 mg/mL and 90 mg/mL. In one embodiment, theconcentration of CoQ10 is between 30 mg/mL and 80 mg/mL. In oneembodiment, the concentration of CoQ10 is between 30 mg/mL and 70 mg/mL.In one embodiment, the concentration of CoQ10 is between 30 mg/mL and 60mg/mL. In one embodiment, the concentration of CoQ10 is between 30 mg/mLand 50 mg/mL. In one embodiment, the concentration of CoQ10 is between35 mg/mL and 45 mg/mL. It should be understood that additional rangeshaving any one of the foregoing values as the upper or lower limits arealso intended to be part of this invention, e.g., between 10 mg/mL and50 mg/mL, or between 20 mg/mL and 60 mg/mL.

In certain embodiments, the concentration of CoQ10 in the formulation isabout 10, 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95mg/mL. In one embodiment, the concentration of CoQ10 in the formulationis about 50 mg/mL. In one embodiment, the concentration of CoQ10 in theformulation is about 60 mg/mL. In one embodiment, the concentration ofCoQ10 in the formulation is about 30 mg/mL. In a preferred embodiment,the concentration of CoQ10 in the formulation is about 40 mg/mL. Itshould be understood that ranges having any one of these values as theupper or lower limits are also intended to be part of this invention,e.g. between 37 mg/mL and 47 mg/mL, or between 31 mg/mL and 49 mg/mL.

It is understood that formulations can similarly be prepared containingCoQ10 precursors, metabolites, and related compounds.

V. Treatment of Cancer

Formulations of the present disclosure may be utilized for the treatmentof cancer including primary and secondary tumors. Accordingly, thepresent invention provides methods of treating or preventing cancer in asubject, comprising administering the formulations of the invention tothe subject in an amount sufficient to treat or prevent the cancer,thereby treating or preventing cancer. The formulations of the inventionmay also be utilized for inhibiting tumor cell growth. Accordingly, theinvention further provides methods of inhibiting tumor cell growth in asubject, comprising administering the formulations of the invention tothe subject, such that tumor cell growth is inhibited. The inventionalso provides embodiments in which the formulation is administered tothe subject by a route other than direct administration to the CNS,i.e., not intrathecally, intracranially, intraventricularly,intramedullaryly, or intraocularly. In certain embodiments, the agent isnot administered into the CNS tumor. In certain embodiments, the subjectis a human subject.

Such formulations may include the hydrophobic therapeutic agent, e.g.,CoQ10, its metabolites, or CoQ10 related compounds, in apharmaceutically acceptable carrier. In some embodiments, such aformulation may include from about 0.001% to about 20% (w/w) of CoQ10,more preferably between about 0.01% and about 15% and even morepreferably between about 0.1% to about 10% (w/w) of CoQ10. In oneembodiment a formulation includes about 4% (w/w) of CoQ10. In oneembodiment a formulation includes about 8% (w/w) of CoQ10. In variousembodiments, the formulation includes about 0.1%, 0.2%, 0.3%, 0.4%,0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% (w/w) of CoQ10, orany range bracketed by those values. As also noted herein, compositionsof the present disclosure may be in a liquid form, capable ofintroduction into a subject by any means or route of administrationwithin the purview of those skilled in the art. For example,compositions may be administered by routes of administration including,but not limited to, intravenous, intratumoral, combinations thereof, andthe like.

In certain embodiments of the invention, methods are provided fortreating or preventing cancer in a human by intravenously administeringa CoQ10, CoQ10 precursor, metabolite, or related compound formulation tothe human such that treatment or prevention occurs, wherein the human isadministered a dose of the formulation such that, preferably, CoQ10 isadministered in the range of about 0.5 mg/kg to about 10,000 mg/kg,about 5 mg/kg to about 5,000 mg/kg, about 10 mg/kg to about 3,000 mg/kg.In one embodiment, the formulation is administered such that,preferably, CoQ10 is administered in the range of about 10 mg/kg toabout 1,400 mg/kg. In one embodiment, the formulation is administeredsuch that, preferably, CoQ10 is administered in the range of about 10mg/kg to about 650 mg/kg. In one embodiment, the formulation isadministered such that, preferably, CoQ10 is administered in the rangeof about 10 mg/kg to about 200 mg/kg. In various embodiments, theformulation is administered such that, preferably, CoQ10 is administeredat a dose of about 2 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 56mg/kg, 57 mg/kg, 58 mg/kg, 59 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75mg/kg, 76 mg/kg, 77 mg/kg, 78 mg/kg, 79 mg/kg, 80 mg/kg, 85 mg/kg, 90mg/kg, 95 mg/kg, 100 mg/kg, 101 mg/kg, 102 mg/kg, 103 mg/kg, 104 mg/kg,105 mg/kg, 106 mg/kg, 107 mg/kg, 108 mg/kg, 109 mg/kg, 110 mg/kg, 120mg/kg, 130 mg/kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 170 mg/kg, 180 mg/kg,190 mg/kg or 200 mg/kg. In various embodiments, the formulation isadministered such that, preferably, CoQ10 is administered at a dose ofat least 2 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 56 mg/kg, 57mg/kg, 58 mg/kg, 59 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 76mg/kg, 77 mg/kg, 78 mg/kg, 79 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95mg/kg, 100 mg/kg, 101 mg/kg, 102 mg/kg, 103 mg/kg, 104 mg/kg, 105 mg/kg,106 mg/kg, 107 mg/kg, 108 mg/kg, 109 mg/kg, 110 mg/kg, 120 mg/kg, 130mg/kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 170 mg/kg, 180 mg/kg, 190 mg/kgor 200 mg/kg, wherein the dose does not result in any limitingtoxicities. It should be understood that ranges having any one of thesevalues as the upper or lower limits are also intended to be part of thisinvention, e.g., about 50 mg/kg to about 200 mg/kg, or about 650 mg/kgto about 1400 mg/kg, or about 55 mg/kg to about 110 mg/kg. In oneembodiment the administered dose is at least about 1 mg/kg, at leastabout 5 mg/kg, at least about 10 mg/kg, at least about 12.5 mg/kg, atleast about 20 mg/kg, at least about 25 mg/kg, at least about 30 mg/kg,at least about 35 mg/kg, at least about 40 mg/kg, at least about 45mg/kg, at least about 50 mg/kg, at least about 55 mg/kg, at least about60 mg/kg, at least about 75 mg/kg, at least about 100 mg/kg, at leastabout 125 mg/kg, at least about 150 mg/kg, at least about 175 mg/kg, atleast about 200 mg/kg, at least about 300 mg/kg, or at least about 400mg/kg. In certain embodiments, the administered dose is no more thanabout 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg,about 75 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about175 mg/kg, about 200 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500mg/kg, about 600 mg/kg, about 700 mg/kg, about 800 mg/kg, about 900mg/kg, about 1000 mg/kg, about 1100 mg/kg, about 1200 mg/kg, or about1300 mg/kg. It is understood that any of the lower limit values andupper limit values can be combined to create a range. In certainembodiments, the administered dose is at least 75 mg/kg or 100 mg/kg orthe rat equivalent to about, at least, 12.2 or 16.2 mg/kg/day in humans,or at least 85 mg/kg over a week period, or at least 113 mg/kg over aweek period.

In one embodiment, the formulation, preferably, the CoQ10 formulation,is administered one time per week. In one embodiment, the formulation,preferably, the CoQ10 formulation, is administered 3 times per week. Inanother embodiment, the formulation, preferably, the CoQ10 formulation,is administered 5 times per week. In one embodiment, the formulation,preferably, the CoQ10 formulation, is administered once per day. In someembodiments, where the formulation is an IV formulation administered byinfusion, the dosage is administered by infusion over about 1 hour, 2hours, 3 hours, 4 hours or longer. In one embodiment, the IV formulationis administered by infusion over about 4 hours.

In certain embodiments, the formulation, preferably, a CoQ10formulation, can be administered in one or more cycles. For example, theCoQ10 can be administered for 2, 3, 4, 5, 6, 7, 8, or more weeksconsecutively, and then not administered for a period of 1, 2, 3, 4, ormore weeks, providing a cycle of administration. The number of cycles ofadministration depends, for example, on the response of the subject, theseverity of disease, and other therapeutic interventions used on thesubject.

In another embodiment, the formulation, preferably, a CoQ10 formulation,is administered in the form of a CoQ10 IV formulation at a dosage ofbetween about 10 mg/kg and about 10,000 mg/kg of CoQ10, about 20 mg/kgto about 5000 mg/kg, about 50 mg/kg to about 3000 mg/kg, about 100 mg/kgto about 2000 mg/kg, about 200 mg/kg to about 1000 mg/kg, about 300mg/kg to about 500 mg/kg, or about 55 mg/kg to about 110 mg/kg whereinthe CoQ10 formulation comprises between about 1% and 10% of CoQ10. Inone embodiment, the CoQ10 formulation comprises about 4% of CoQ10. Inone embodiment, the CoQ10 IV formulation comprises about 8% of CoQ10. Inother embodiments, the CoQ10 IV formulation comprises about 0.1%, 0.2%,0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%,4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5% or 10% ofCoQ10. It should be understood that ranges having any one of thesevalues as the upper or lower limits are also intended to be part of thisinvention.

In the treatment of CNS cancers, the formulations may be in apharmaceutically acceptable carrier that may be administered in atherapeutically effective amount to a subject as either a mono-therapy,in combination with at least one other chemotherapeutic agent for agiven indication, in combination with radiotherapy, following surgicalintervention to radically remove a tumor, in combination with otheralternative and/or complementary acceptable treatments for cancer, andthe like.

In general, the CoQ10 formulation described herein may be used toprophylactically or therapeutically treat any neoplasm. In a particularembodiment, the formulation is used to treat CNS tumors including bothprimary and secondary CNS tumors. It is understood that those sufferingfrom a secondary CNS neoplasm are likely suffering from neoplasia at oneor more other sites in the body. In one embodiment, the CoQ10formulations described herein may be used to treat a chloroleukemia,e.g., a secondary or metastatic chloroleukemia, e.g., that presents,migrates or metastasizes to the central nervous system.

In certain embodiments, the effect CoQ10 may have on cancer cells maydepend, in part, on the various states of metabolic and oxidative fluxexhibited by the cancer cells. CoQ10 may be utilized to interrupt and/orinterfere with the conversion of an oncogenic cell's dependency ofglycolysis and increased lactate utility. As it relates to a cancerstate, this interference with the glycolytic and oxidative flux of thetumor microenvironment may influence apoptosis and angiogenesis in amanner which reduces the development of a cancer cell. In someembodiments, the interaction of CoQ10 with glycolytic and oxidative fluxfactors may enhance the ability of CoQ10 to exert its restorativeapoptotic effect in cancer. While the present disclosure has focused onCoQ10 and its metabolites, other compounds related to CoQ10 which may beadministered instead of, or in combination with, CoQ10 include, but arenot limited to, benzoquinones, isoprenoids, farnesols, farnesyl acetate,farnesyl pyrophosphate, 1-phenylalanine, d-phenylalanine,dl-phenylalanine, 1-tyrosine, d-tyrosine, dl-tyrosine,4-hydroxy-phenylpyruvate, 4-hydroxy-phenyllactate, 4-hydroxy-cinnamate,dipeptides and tripeptides of tyrosine or phenylalanine,3,4-dihydroxymandelate, 3- methoxy-4-hydroxyphenylglycol,3-methoxy-4-hydroxymandelate, vanillic acid, phenylacetate, pyridoxine,S-adenosyl methionine, panthenol, mevalonic acid, isopentylpyrophosphate, phenylbutyrate, 4-hydroxy-benzoate, decaprenylpyrophosphate, beta-hydroxybutyrate, 3-hydroxy-3-methyl-glutarate,acetylcarnitine, acetoacetylcarnitine, acetylglycine,acetoacetylglycine, carnitine, acetic acid, pyruvic acid,3-hydroxy-3-methylglutarylcarnitine, all isomeric forms of serine,alanine, cysteine, glycine, threonine, hydroxyproline, lysine,isoleucine, and leucine, even carbon number C4 to C8 fatty acids(butyric, caproic, caprylic, capric, lauric, myristic, palmitic, andstearic acids) salts of carnitine and glycine, e.g., palmitoylcarnitineand palmitoylglycine, and 4-hydroxy-benzoate polyprenyltransferase, anysalts of these compounds, as well as any combinations thereof, and thelike.

In one embodiment, administration of CoQ10 as described herein, reducesCNS tumor size, inhibits CNS tumor growth and/or prolongs the survivaltime of a CNS tumor-bearing subject as compared to an appropriatecontrol. Accordingly, this invention also relates to a method oftreating CNS tumors in a human or other animal by administering to suchhuman or animal an effective, non-toxic amount of CoQ10. For example, byadministering an effective dose by IV administration. Or, for example,by administering an effective dose by topical administration. Oneskilled in the art would be able, by routine experimentation with theguidance provided herein, to determine what an effective, non-toxicamount of CoQ10 would be for the purpose of treating malignancies. Forexample, a therapeutically active amount of CoQ10 may vary according tofactors such as the disease stage (e.g., stage I versus stage IV), age,sex, medical complications (e.g., immunosuppressed conditions ordiseases) and weight of the subject, and the ability of the CoQ10 toelicit a desired response in the subject. The dosage regimen may beadjusted to provide the optimum therapeutic response. For example,several divided doses may be administered daily, or the dose may beproportionally reduced as indicated by the exigencies of the therapeuticsituation.

In certain embodiments of the invention, the methods further include atreatment regimen which includes any one of or a combination of surgery,radiation, hormone therapy, antibody therapy, therapy with growthfactors, cytokines, and chemotherapy.

It is understood that such treatment methods can similarly be performedby administration of CoQ10 precursors, metabolites, and relatedcompounds.

VI. Prevention and Treatment of Secondary Malignancies

While prognosis of childhood cancers, particularly childhood leukemiasis quite high, long-term survivors are increasingly experiencing lateeffects of treatment. For example, a study of 9720 children given adiagnosis of acute lymphoblastic leukemia in 1972-1988 treated with thestandard of care were found to have a 7 fold excess of all cancers and a22-fold excess of neoplasms of the CNS at a median follow-up of 4.7years (Neglia et al., NEJM, 325:1330-1336, 1991, incorporated herein byreference). The British Childhood Cancer Survivor Study, a national,population-based, cohort study of 17,980 individuals surviving at least5 years after diagnosis of childhood cancer identified 247 secondaryprimary neoplasms (SPNs) of the CNS. In the study, the risk ofmeningioma was found to increase rapidly with increased dose ofradiation to meningeal tissue, up to a 479-fold increase, and withincreased dose of intrathecal methotrexate, up to a 36-fold increase, ascompared to the general population (Taylor et al., J Clin Oncol28:5287-5293, 2010, incorporated herein by reference). Longer periods offollow-up revealed even greater incidences of secondary tumors,particularly secondary CNS tumors. For example, a study of 1612consecutively enrolled patients treated for acute lymphocytic leukemia(ALL) had a cumulative incidence of brain tumors at 20 years of 1.39%(Walter et al., J Clin Oncol., 16:3761-3767, 1998, incorporated hereinby reference). Hijiya et al., 2007, (JAMA, 297:1207-1215, incorporatedherein by reference) reported on a retrospective study of 2169 patientswith acute lymphoblastic leukemia treated between 1962 and 1998 whoachieved complete remission and had a median follow-up time of 18.7years (range, 2.4-41.3 years). Secondary neoplasms developed as thefirst event in 123 patients and comprised 46 myeloid malignancies, 3lymphomas, 14 basal cell carcinomas, 16 other carcinomas, 6 sarcomas, 16meningiomas, and 22 other brain tumors providing a cumulative incidenceof secondary neoplasm was 4.17% (SE, 0.46%) at 15 years and increasedsubstantially after 20 years, reaching 10.85% (SE, 1.27%) at 30 years.The cumulative incidence of each tumor type at 30 years was 2.19% (SE,0.32%) for myeloid malignancy, 0.17% (SE, 0.10%) for lymphoma, 3.00%(SE, 0.59%) for brain tumor, 4.91% (SE, 1.04%) for carcinoma, and 0.57%(SE, 0.37%) for sarcoma. The cumulative incidence of secondary neoplasmswas demonstrated to increase steadily over 30 years after treatment ofALL.

Secondary tumors are also observed in subjects treated for adult tumors.However, due to the long latency period, such tumors are less frequentlyobserved.

In certain embodiments, the CoQ10 compounds provided herein can be usedto prevent and/ or treat secondary tumors after treatment and remissionof the primary tumors. In certain embodiments, the methods can be usedfor the prevention of all types of secondary tumors. In certainembodiments, the methods can be used for the prevention of secondary CNStumors. In certain embodiments, the methods can be used for thetreatment of secondary tumors. The secondary tumors include, forexample, secondary tumors of the CNS. The secondary tumors of the CNScan be identified, for example, by monitoring a subject who is at highrisk for development of a secondary CNS tumor, e.g., a subject who is inremission from a pediatric tumor, particularly a pediatric leukemia,particularly when the subject was treated with radiation to the CNS orwith chemotherapeutic agents delivered to the CNS, for the developmentof a CNS abnormality. The CNS abnormality can be detected by functionaltesting, reporting or identification of CNS abnormalities, e.g.,headache, seizure, or imaging analysis.

The Examples demonstrate that the CoQ10 compounds provided herein areuseful for the treatment of such secondary tumors. Specifically, in theexamples, leukemia was induced in rats that were subsequently treatedfor the leukemia. As a result of the treatment, about half of the ratssurvived and entered remission. However, over time, about 20% of thesurviving rats developed CNS tumors as demonstrated by the appearance ofCNS abnormalities. That is, the rats developed secondary CNS tumorswhich were effectively treated with the CoQ10 compounds provided herein.

As the CoQ10 compounds provided herein do not demonstrate significanttoxicities, the compounds could be used to prevent the development ofsecondary tumors, including secondary CNS tumors, by administration of aCoQ10 compound to a subject at the conclusion of treatment for theprimary tumor, e.g., the primary leukemia. Administration of the CoQ10compound can be initiated at any time after the conclusion of thetreatment of the leukemia, e.g., at a specific time interval, e.g., onemonth, six months, one year, two years, three years, five years, tenyears, etc.; or after a specific event, e.g., after confirmation ofremission, or a certain time interval after confirmation of remission,e.g., one month, six months, one year, two years, three years, fiveyears, ten years, etc. after remission. The CoQ10 compounds can beadministered using the methods and formulations provided herein.

VII. Combination Therapies

In certain embodiments, the formulations of the invention, e.g., theCoQ10 formulations, can be used in combination therapy with at least oneother therapeutic agent. In preferred embodiments, CoQ10 is administeredin an amount that would be therapeutically effective if delivered alone,i.e., CoQ10 is a therapeutic agent, not predominantly an agent toameliorate side effects of other chemotherapy or other cancertreatments. CoQ10 and/or pharmaceutical formulations thereof and theother therapeutic agent can act additively or, more preferably,synergistically. In one embodiment, CoQ10 and/or a formulation thereofis administered concurrently with the administration of anothertherapeutic agent. In another embodiment, a compound and/orpharmaceutical formulation thereof is administered prior or subsequentto administration of another therapeutic agent. In one embodiment, theCoQ10 and additional therapeutic agent active synergistically. In oneembodiment, the CoQ10 and additional therapeutic agent act additively.

In one embodiment, the therapeutic methods of the invention furthercomprise administration of one or more additional agents, e.g., one ormore therapeutic agents. For example, in one embodiment, an additionalagent for use in the therapeutic methods of the invention is achemotherapeutic agent.

Chemotherapeutic agents generally belong to various classes including,for example: 1. Topoisomerase II inhibitors (cytotoxic antibiotics),such as the anthracyclines/anthracenediones, e.g., doxorubicin,epirubicin, idarubicin and nemorubicin, the anthraquinones, e.g.,mitoxantrone and losoxantrone, and the podophillotoxines, e.g.,etoposide and teniposide; 2. Agents that affect microtubule formation(mitotic inhibitors), such as plant alkaloids (e.g., a compoundbelonging to a family of alkaline, nitrogen-containing molecules derivedfrom plants that are biologically active and cytotoxic), e.g., taxanes,e.g., paclitaxel and docetaxel, and the vinka alkaloids, e.g.,vinblastine, vincristine, and vinorelbine, and derivatives ofpodophyllotoxin; 3. Alkylating agents, such as nitrogen mustards,ethyleneimine compounds, alkyl sulphonates and other compounds with analkylating action such as nitrosoureas, dacarbazine, cyclophosphamide,ifosfamide and melphalan; 4. Antimetabolites (nucleoside inhibitors),for example, folates, e.g., folic acid, fiuropyrimidines, purine orpyrimidine analogues such as 5-fluorouracil, capecitabine, gemcitabine,methotrexate, and edatrexate; 5. Topoisomerase I inhibitors, such astopotecan, irinotecan, and 9-nitrocamptothecin, camptothecinderivatives, and retinoic acid; and 6. Platinum compounds/complexes,such as cisplatin, oxaliplatin, and carboplatin; Exemplarychemotherapeutic agents for use in the methods of the invention include,but are not limited to, amifostine (ethyol), cisplatin, dacarbazine(DTIC), dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carrnustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), doxorubicin lipo (doxil), gemcitabine (gemzar),daunorubicin, daunorubicin lipo (daunoxome), procarbazine, mitomycin,cytarabine, etoposide, methotrexate, 5-fluorouracil (5-FU), vinblastine,vincristine, bleomycin, paclitaxel (taxol), docetaxel (taxotere),aldesleukin, asparaginase, busulfan, carboplatin, cladribine,camptothecin, CPT-I 1, 1O-hydroxy-7-ethyl-camptothecin (SN38),dacarbazine, S-I capecitabine, ftorafur, 5′deoxyflurouridine, UFT,eniluracil, deoxycytidine, 5-azacytosine, 5-azadeoxycytosine,allopurinol, 2-chloro adenosine, trimetrexate, aminopterin,methylene-10-deazaaminopterin (MDAM), oxaplatin, picoplatin,tetraplatin, satraplatin, platinum-DACH, ormaplatin, CI-973, JM-216, andanalogs thereof, epirubicin, etoposide phosphate, 9-aminocamptothecin,10, 11-methylenedioxycamptothecin, karenitecin, 9-nitrocamptothecin, TAS103, vindesine, L-phenylalanine mustard, ifosphamidemefosphamide,perfosfamide, trophosphamide carmustine, semustine, epothilones A-E,tomudex, 6-mercaptopurine, 6-thioguanine, amsacrine, etoposidephosphate, karenitecin, acyclovir, valacyclovir, ganciclovir,amantadine, rimantadine, lamivudine, zidovudine, bevacizumab,trastuzumab, rituximab, 5-Fluorouracil, Capecitabine, Pentostatin,Trimetrexate, Cladribine, floxuridine, fludarabine, hydroxyurea,ifosfamide, idarubicin, mesna, irinotecan, mitoxantrone, topotecan,leuprolide, megestrol, melphalan, mercaptopurine, plicamycin, mitotane,pegaspargase, pentostatin, pipobroman, plicamycin, streptozocin,tamoxifen, teniposide, testolactone, thioguanine, thiotepa, uracilmustard, vinorelbine, chlorambucil, cisplatin, doxorubicin, paclitaxel(taxol), bleomycin, mTor, epidermal growth factor receptor (EGFR), andfibroblast growth factors (FGF) and combinations thereof which arereadily apparent to one of skill in the art based on the appropriatestandard of care for a particular tumor or cancer.

In another embodiment, an additional agent for use in the combinationtherapies of the invention is a biologic agent.

Biologic agents (also called biologics) are the products of a biologicalsystem, e.g., an organism, cell, or recombinant system. Examples of suchbiologic agents include nucleic acid molecules (e.g., antisense nucleicacid molecules), interferons, interleukins, colony-stimulating factors,antibodies, e.g., monoclonal antibodies, anti-angiogenesis agents, andcytokines. Exemplary biologic agents are discussed in more detail belowand generally belong to various classes including, for example: 1.Hormones, hormonal analogues, and hormonal complexes, e.g., estrogensand estrogen analogs, progesterone, progesterone analogs and progestins,androgens, adrenocorticosteroids, antiestrogens, antiandrogens,antitestosterones, adrenal steroid inhibitors, and anti-leuteinizinghormones; and 2. Enzymes, proteins, peptides, polyclonal and/ormonoclonal antibodies, such as interleukins, interferons, colonystimulating factor, etc.

In one embodiment, the biologic is an interfereon. Interferons (IFN) area type biologic agent that naturally occurs in the body. Interferons arealso produced in the laboratory and given to cancer patients inbiological therapy. They have been shown to improve the way a cancerpatient's immune system acts against cancer cells.

Interferons may work directly on cancer cells to slow their growth, orthey may cause cancer cells to change into cells with more normalbehavior. Some interferons may also stimulate natural killer cells (NK)cells, T cells, and macrophages which are types of white blood cells inthe bloodstream that help to fight cancer cells.

In one embodiment, the biologic is an interleukin. Interleukins (IL)stimulate the growth and activity of many immune cells. They areproteins (cytokines and chemokines) that occur naturally in the body,but can also be made in the laboratory.

Some interleukins stimulate the growth and activity of immune cells,such as lymphocytes, which work to destroy cancer cells.

In another embodiment, the biologic is a colony-stimulating factor.

Colony-stimulating factors (CSFs) are proteins given to patients toencourage stem cells within the bone marrow to produce more blood cells.The body constantly needs new white blood cells, red blood cells, andplatelets, especially when cancer is present. CSFs are given, along withchemotherapy, to help boost the immune system. When cancer patientsreceive chemotherapy, the bone marrow's ability to produce new bloodcells is suppressed, making patients more prone to developinginfections. Parts of the immune system cannot function without bloodcells, thus colony-stimulating factors encourage the bone marrow stemcells to produce white blood cells, platelets, and red blood cells.

With proper cell production, other cancer treatments can continueenabling patients to safely receive higher doses of chemotherapy.

In another embodiment, the biologic is an antibody. Antibodies, e.g.,monoclonal antibodies, are agents, produced in the laboratory, that bindto cancer cells.

Monoclonal antibody agents do not destroy healthy cells. Monoclonalantibodies achieve their therapeutic effect through various mechanisms.They can have direct effects in producing apoptosis or programmed celldeath. They can block growth factor receptors, effectively arrestingproliferation of tumor cells. In cells that express monoclonalantibodies, they can bring about anti-idiotype antibody formation.

Examples of antibodies which may be used in the combination treatment ofthe invention include anti-CD20 antibodies, such as, but not limited to,cetuximab, Tositumomab, rituximab, and Ibritumomab. Anti-HER2 antibodiesmay also be used in combination with an environmental influencer for thetreatment of cancer. In one embodiment, the anti-HER2 antibody isTrastuzumab (Herceptin). Other examples of antibodies which may be usedin combination with an environmental influencer for the treatment ofcancer include anti-CD52 antibodies (e.g., Alemtuzumab), anti-CD-22antibodies (e.g., Epratuzumab), and anti-CD33 antibodies (e.g.,Gemtuzumab ozogamicin). Anti-VEGF antibodies may also be used incombination with an environmental influencer for the treatment ofcancer. In one embodiment, the anti-VEGF antibody is bevacizumab. Inother embodiments, the biologic agent is an antibody which is ananti-EGFR antibody e.g., cetuximab. Another example is theanti-glycoprotein 17-1A antibody edrecolomab. Numerous other anti-tumorantibodies are known in the art and would be understood by the skilledartisan to be encompassed by the present invention.

In another embodiment, the biologic is a cytokine. Cytokine therapy usesproteins (cytokines) to help a subject's immune system recognize anddestroy those cells that are cancerous. Cytokines are produced naturallyin the body by the immune system, but can also be produced in thelaboratory. This therapy is used with advanced melanoma and withadjuvant therapy (therapy given after or in addition to the primarycancer treatment). Cytokine therapy reaches all parts of the body tokill cancer cells and prevent tumors from growing.

In another embodiment, the biologic is a fusion protein. For example,recombinant human Apo2L/TRAIL (GENETECH) may be used in a combinationtherapy. Apo2/TRAIL is the first dual pro-apoptotic receptor agonistdesigned to activate both pro-apoptotic receptors DR4 and DR5, which areinvolved in the regulation of apoptosis (programmed cell death).

In one embodiment, the biologic is an antisense nucleic acid molecule.

As used herein, an “antisense” nucleic acid comprises a nucleotidesequence which is complementary to a “sense” nucleic acid encoding aprotein, e.g., complementary to the coding strand of a double-strandedcDNA molecule, complementary to an mRNA sequence or complementary to thecoding strand of a gene. Accordingly, an antisense nucleic acid canhydrogen bond to a sense nucleic acid.

In one embodiment, a biologic agent is an siRNA molecule, e.g., of amolecule that enhances angiogenesis, e.g., bFGF, VEGF and EGFR. In oneembodiment, a biologic agent that inhibits angiogenesis mediates RNAi.RNA interference (RNAi) is a post-transcriptional, targetedgene-silencing technique that uses double-stranded RNA (dsRNA) todegrade messenger RNA (mRNA) containing the same sequence as the dsRNA(Sharp, P. A. and Zamore, P. D. 287, 2431-2432 (2000); Zamore, P. D., etal. Cell 101, 25-33 (2000). Tuschl, T. et al. Genes Dev. 13, 3191-3197(1999); Cottrell T R, and Doering T L. 2003. Trends Microbiol. 11:37-43;Bushman F. 2003. MoI Therapy. 7:9-10; McManus M T and Sharp P A. 2002.Nat Rev Genet. 3.737-47). The process occurs when an endogenousribonuclease cleaves the longer dsRNA into shorter, e.g., 21- or22-nucleotide-long RNAs, termed small interfering RNAs or siRNAs. Thesmaller RNA segments then mediate the degradation of the target mRNA.Kits for synthesis of RNAi are commercially available from, e.g. NewEngland Biolabs® or Ambion®. In one embodiment one or more chemistriesfor use in antisense RNA can be employed in molecules that mediate RNAi.

In another embodiment, an antisense nucleic acid of the invention is acompound that mediates RNAi. RNA interfering agents include, but are notlimited to, nucleic acid molecules including RNA molecules which arehomologous to the target gene or genomic sequence, “short interferingRNA” (siRNA), “short hairpin” or “small hairpin RNA” (shRNA), and smallmolecules which interfere with or inhibit expression of a target gene byRNA interference (RNAi). RNA interference is a post-transcriptional,targeted gene-silencing technique that uses double-stranded RNA (dsRNA)to degrade messenger RNA (mRNA) containing the same sequence as thedsRNA (Sharp, P. A. and Zamore, P. D. 287, 2431-2432 (2000); Zamore, P.D., et al. Cell 101, 25-33 (2000). Tuschl, T. et al. Genes Dev. 13,3191-3197 (1999)). The process occurs when an endogenous ribonucleasecleaves the longer dsRNA into shorter, 21- or 22-nucleotide-long RNAs,termed small interfering RNAs or siRNAs. The smaller RNA segments thenmediate the degradation of the target mRNA. Kits for synthesis of RNAiare commercially available from, e.g. New England Biolabs and Ambion. Inone embodiment one or more of the chemistries described above for use inantisense RNA can be employed.

Exemplary biologic agents for use in the methods of the inventioninclude, but are not limited to, gefitinib (Iressa), anastrazole,diethylstilbesterol, estradiol, premarin, raloxifene, progesterone,norethynodrel, esthisterone, dimesthisterone, megestrol acetate,medroxyprogesterone acetate, hydroxyprogesterone caproate,norethisterone, methyltestosterone, testosterone, dexamthasone,prednisone, Cortisol, solumedrol, tamoxifen, fulvestrant, toremifene,aminoglutethimide, testolactone, droloxifene, anastrozole, bicalutamide,flutamide, nilutamide, goserelin, flutamide, leuprolide, triptorelin,aminoglutethimide, mitotane, goserelin, cetuximab, erlotinib, imatinib,Tositumomab, Alemtuzumab, Trastuzumab, Gemtuzumab, Rituximab,Ibritumomab tiuxetan, Bevacizumab, Denileukin diftitox, Daclizumab,interferon alpha, interferon beta, anti-4-1BB, anti-4-1BBL, anti-CD40,anti-CD 154, anti- OX40, anti-OX40L, anti-CD28, anti-CD80, anti-CD86,anti-CD70, anti-CD27, anti-HVEM, anti-LIGHT, anti-GITR, anti-GITRL,anti-CTLA-4, soluble OX40L, soluble 4-IBBL, soluble CD154, solubleGITRL, soluble LIGHT, soluble CD70, soluble CD80, soluble CD86, solubleCTLA4-Ig, GVAX®, and combinations thereof which are readily apparent toone of skill in the art based on the appropriate standard of care for aparticular tumor or cancer. The soluble forms of agents may be made as,for example fusion proteins, by operatively linking the agent with, forexample, Ig-Fc region.

It should be noted that more than one additional agent, e.g., 1, 2, 3,4, 5, may be administered in combination with the CoQ10 formulationsprovided herein. For example, in one embodiment two chemotherapeuticagents may be administered in combination with CoQ10. In anotherembodiment, a chemotherapeutic agent, a biologic agent, and CoQ10 may beadministered. Appropriate doses and routes of administration of thechemotherapeutic agents provided herein are known in the art.

Reference will now be made in detail to preferred embodiments of theinvention. While the invention will be described in conjunction with thepreferred embodiments, it will be understood that it is not intended tolimit the invention to those preferred embodiments. To the contrary, itis intended to cover alternatives, modifications, and equivalents as maybe included within the spirit and scope of the invention as defined bythe appended claims.

EXAMPLES Example 1 Treatment of Central Nervous System ChloroleukemiasUsing Coenzyme Q10

A model of CNS chloroleukemia was created using Fischer 344 rats, inwhich chloroleukemic cells were injected into the rats as newborns andlipopolysaccharide (LPS) was given as a first-line of treatment. Thecure rate with this regimen was approximately 50%, and approximately 10%of survivors developed CNS leukemia as judged by their motor skills andthe presence of quadriplegia and paraplegia.

For this study, 2400 Fischer 344 neonates were injected with thechloroleukemic cell line MIAC51 and treated with LPS. All animals withovert signs of leukemia, i.e., systemic disease, were sacrificed by day26. By day 35, survivors started exhibiting CNS abnormalities suggestingthat the tumor was localized to the CNS. Of that cohort, 150 animalswere selected with hind leg paraplegia on day 40, see FIGS. 1A and 1B.These animals were then re-randomized into 5 groups: group 1 received notreatment, group 2 received excipient control IV, group 3 received 5mg/kg CoQ10 IV (i.e., 15 mg/kg/day), group 4 received 10 mg/kg IV (i.e.,30 mg/kg/day), and group 5 received 25 mg/kg IV (i.e., 75 mg/kg/day) for4 weeks, 3 times daily.

Rats in groups 1, 2, 3 and 4 did not exhibit any signs of improvementand were sacrificed due to metastatic malignancy and severe CNSabnormalities, e.g., resulting in decreased muscle control, lack ofcoordination, weakness, paralysis, difficulties in walking thatprevented the rats from eating or performing self care (FIG. 2). Thesefindings were recorded by MRI positive for tumor cells. In sharpcontrast, animals injected with 25 mg/kg IV three times per day (i.e.,75 mg/kg/day) exhibited a significant recovery of their motor skills andregained their ability to walk. MRI distinctly shows the lack of tumorcells in this group (FIGS. 3A and B). Taken together, these resultsstrongly indicate that CoQ10 is an effective treatment for CNS leukemiaand may also be an effective prophylactic agent to prevent theextravasation of leukemic cells in the CNS, thereby preventing,delaying, or limiting the formation of secondary tumors.

Example 2 Long Term Effect of CoQ10 Treatment of Central Nervous SystemChloroleukemias

The model of CNS chloroleukemia in Fischer 344 rats provided in Example1 was used for long term studies of the treatment of metastatic,leukemic CNS tumors. As in Example 1 chloroleukemic cells were injectedinto the rats as newborns and lipopolysaccharide (LPS) was given as afirst-line of treatment. The cure rate with this regimen wasapproximately 50%, and approximately 10% of survivors developed CNSleukemia as judged by their motor skills and the presence ofquadriplegia and paraplegia.

For this study of long term effect of CoQ10 on CNS leukemia, 300paraplegic animals with overt CNS leukemia were randomized into twogroups of 150 animals each. Group one received a saline control. Grouptwo received 100 mg/kg CoQ10 once daily starting on day 1 through day 28(first cycle). The second cycle started on day 35 and continued throughday 62. In this study, animals received two cycles of 28 days of CoQ10.

Rats in the control groups did not exhibit any signs of improvement andwere sacrificed due to metastatic malignancy and severe CNSabnormalities, e.g., resulting in decreased muscle control, lack ofcoordination, weakness, paralysis, difficulties in walking thatprevented the rats from eating or performing self care (FIG. 4). Insharp contrast, animals injected with 100 mg/kg IV exhibited asignificant recovery of their motor skills and regained their ability towalk. On days 173 and 195 five (5) animals which were treated with 100mg/kg CoQ10 were sacrificed for necropsy and pathological analysis. Noevidence of chloroleukemia or CNS tumors were found

Taken together, these results strongly indicate that CoQ10 is aneffective treatment for CNS leukemia and may also be an effectiveprophylactic agent to prevent the extravasation of leukemic cells in theCNS, thereby preventing, delaying, or limiting the formation ofsecondary tumors.

We claim:
 1. A method of treating a central nervous system (CNS) tumorin a subject exhibiting at least one CNS abnormality comprisingadministering to the subject a composition comprising a Coenzyme Q10(CoQ10) compound, thereby treating the CNS tumor.
 2. The method of claim1, wherein a CNS abnormality is selected from the group consisting of aheadache, a seizure, a change in memory, loss of short term memory, achange in temperament, sudden onset of panic attacks induced by familiarsituations, a change in intellectual function, inability to do math,inability to find objects in plain sight; confusion, disorientation,becoming lost in a familiar location; blurred vision, loss of vision,loss of peripheral vision, double vision, dizziness, hearing problems,ringing in ears, buzzing in ears, decreased muscle control, lack ofcoordination, decreased sensation, weakness, paralysis, paraplegia,quadriplegia, difficulty with walking, change in gait, difficulty withspeech, and balance problems.
 3. The method of claim 1, whereintreatment results in amelioration of at least one CNS abnormality. 4.The method of claim 3, wherein at least one CNS abnormality comprises atleast 2 CNS abnormalities.
 5. The method of claim 3, wherein at leastone CNS abnormality comprises 3-10 CNS abnormalities. 6-7. (canceled) 8.A method of prevention or treatment of a secondary CNS tumor from aprimary tumor in a subject comprising administering to the subject acomposition comprising a Coenzyme Q10 (CoQ10) compound, therebypreventing or treating the secondary CNS tumor.
 9. The method of claim8, wherein the primary tumor is a pediatric tumor.
 10. The method ofclaim 9, wherein the pediatric tumor is a leukemia.
 11. The method ofclaims 8, wherein the primary tumor was treated with CNS radiation. 12.The method of claim 8, wherein the primary tumor was treated byadministration of a chemotherapeutic agent to the CNS.
 13. (canceled)14. The method of claim 8, further comprising monitoring the subject fordevelopment of a secondary CNS tumor.
 15. The method of claim 8, whereinthe subject is in remission for the primary tumor.
 16. The method ofclaim 8, wherein the secondary tumor is identified at least one yearafter treatment of the primary tumor is concluded.
 17. The method ofclaim 8, wherein the secondary tumor is identified at least three yearsafter treatment of the primary tumor is concluded.
 18. The method ofclaim 8, wherein the secondary tumor is identified at least five yearsafter treatment of the primary tumor is concluded.
 19. The method ofclaim 8, wherein the secondary tumor is identified at least ten yearsafter treatment of the primary tumor is concluded.
 20. The method ofclaim 1, wherein the CoQ10 compound is CoQ10. 21-22. (canceled)
 23. Themethod of claim 1, wherein the tumor is a leukemic tumor. 24-25.(canceled)
 26. The method of claim 1, wherein the CoQ10 compound isadministered topically.
 27. The method of claim 1, wherein the CoQ10compound is administered parenterally.
 28. The method of claim 1,wherein the CoQ10 compound is administered by injection or infusion. 29.(canceled)
 30. The method of claim 28, wherein the CoQ10 compound is notadministered directly to the CNS.
 31. (canceled)
 32. The method of claim1, further comprising administration of an additional agent. 33.(canceled)
 34. The method of claim 32, wherein the additional agent is achemotherapeutic agent for treatment of a tumor.
 35. The method of claim1, wherein the tumor is further treated with radiation therapy.
 36. Themethod of claim 1, wherein the tumor is further treated with surgery.37. The method of claim 1, wherein the subject is human. 38-49.(canceled)
 50. The method of claim 28, wherein the CoQ10 compound isprovided in an intravenous CoQ10 formulation comprising: an aqueoussolution; a CoQ10 dispersed into a nano-dispersion of particles; and atleast one of a dispersion stabilizing agent and an opsonization reducer;wherein the nano-dispersion of the CoQ10 is dispersed intonano-particles having a mean particle size of less than 200-nm.
 51. Themethod of claim 50, wherein the dispersion stabilizing agent is selectedfrom the group consisting of pegylated castor oil, Cremophor EL,Cremophor RH 40, Pegylated vitamin E, Vitamin E TPGS, andDimyristoylphosphatidyl choline (DMPC).
 52. The method of claim 51,wherein the dispersion stabilizing agent is DMPC.
 53. The method ofclaim 50, wherein the opsonization reducer is selected from the groupconsisting of poloxamers and poloxamines.
 54. The method of claim 53,wherein opsonization reducer is poloxamer
 188. 55. The method of claim54, wherein the opsonization reducer is poloxamer 188 and the dispersionstabilizing agent is DMPC.
 56. The method of claim 55, wherein the CoQ10formulation has a weight-per-volume of the CoQ10, DMPC and poloxamer 188of 4%, 3% and 1.5%, respectively.
 57. (canceled)
 58. The method of claim26, wherein the CoQ10 compound for topical administration is a 3% CoQ10cream comprising: (1) a phase A having C12-15 alkyl benzoate at about4.0% w/w of the composition, cetyl alcohol at about 2.00% w/w of thecomposition, stearyl alcohol at about 1.5% w/w, glyceryl stearate andPEG-100 at about 4.5% w/w; (2) a phase B having glycerin at about 2.00%w/w, propylene glycol at about 1.5% w/w, ethoxydiglycol at about 5.0%w/w, phenoxyethanol at about 0.475% w/w, a carbomer dispersion at about40% w/w, purified water at about 16.7% w/w; (3) a phase C havingtriethanolamine at about 1.3% w/w, lactic acid at about 0.5% w/w, sodiumlactate solution at about 2.0% w/w, water at about 2.5% w/w; (4) a phaseD having titanium dioxide at about 1.0% w/w; and (5) a phase E havingCoQ10 21% concentrate at about 15.0% w/w. 59-62. (canceled)
 63. Themethod of claim 8, wherein the CoQ10 compound is CoQ10.
 64. The methodof claim 8, wherein the CoQ10 compound is administered by injection orinfusion.